Abstract Asthma is a heterogeneous lung disease that has reached epidemic proportions in the U.S.A. The pathogenesis of asthma involves airway epithelial cells that respond to insulting agents and airway smooth muscle cells that constrict because of the disruption of mechanisms that maintain normal bronchial diameter. This latter aspect of the disease is critically important because the morbidity and mortality in asthma stems from airflow limitation due to bronchoconstriction. In order to design more effective therapies for the most crippling manifestation of the disease, we need to identity all systemic regulators, which is our long-term goal. In particular, we have gathered evidence that bone via the hormone osteocalcin favors bronchodilation. Osteocalcin is a newly described hormone that signals following its binding to a specific receptor, Gprc6a. Remarkably, the organ that expresses Gprc6a at the highest level is the lung. This prompted us to study whether osteocalcin exerts any function in the lungs in vivo using mouse models we had generated. Another important reason to do so is that circulating levels of osteocalcin increase during exercise, when bronchodilation is needed to increase ventilation. What we observed is that Osteocalcin-/- (Ocn-/-) and Gprc6a-/- mice have increased airway resistance (Rn) at baseline and airway hyper-responsiveness (AHR) to methacholine, a hallmark of asthma. Remarkably, these two features of the disease develop in the absence of any evidence of airway inflammation. Conversely, mice harboring a gain of function mutation in osteocalcin signaling (Esp-/-) have decreased Rn at baseline and no AHR. Thus, these results dissociate two cardinal manifestations of asthma and further underscore the importance of the endocrine regulation of bronchial diameter. That osteocalcin infusion directly into the brain of Ocn-/- mice did not correct their bronchoconstriction phenotype whereas its systemic administration did, suggest that osteocalcin acts peripherally rather than centrally to control airway diameter. These and other preliminary data presented in the body of this application suggest that bone favors bronchodilation through the hormone osteocalcin after it binds to its cognate receptor Gprc6a in a cell type we intend to identify. Suggesting the cell type, we provide evidence that in absence of osteocalcin signaling there is increased parasympathetic signaling in the lungs. Based on these and on other preliminary data we now propose the following specific aims: To decipher the cellular and molecular mechanism that mediates osteocalcin regulation of bronchodilation To determine whether osteocalcin can improve symptoms of bronchoconstriction in various mouse models of asthma